Exp Mol Med.  2012 Aug;44(8):483-491.

Synergistic induction of cancer cell migration regulated by Gbetagamma and phosphatidylinositol 3-kinase

• Kim EK
• Yun SJ
• Ha JM
• Kim YW
• Jin IH
• Woo DH
• Lee HS
• Ha HK
• Bae SS

Abstract

Phosphatidylinositol 3-kinase (PI3K) is essential for both G protein-coupled receptor (GPCR)- and receptor tyrosine kinase (RTK)-mediated cancer cell migration. Here, we have shown that maximum migration is achieved by full activation of phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) in the presence of Gbetagamma and PI3K signaling pathways. Lysophosphatidic acid (LPA)-induced migration was higher than that of epidermal growth factor (EGF)-induced migration; however, LPA-induced activation of Akt was lower than that stimulated by EGF. LPA-induced migration was partially blocked by either Gbetagamma or RTK inhibitor and completely blocked by both inhibitors. LPA-induced migration was synergistically increased in the presence of EGF and vice versa. In correlation with these results, sphingosine-1-phosphate (S1P)-induced migration was also synergistically induced in the presence of insulin-like growth factor-1 (IGF-1). Finally, silencing of P-Rex1 abolished the synergism in migration as well as in Rac activation. Moreover, synergistic activation of MMP-2 and cancer cell invasion was attenuated by silencing of P-Rex1. Given these results, we suggest that P-Rex1 requires both Gbetagamma and PI3K signaling pathways for synergistic activation of Rac, thereby inducing maximum cancer cell migration and invasion.

Keyword

cell movement; GTP-binding protein beta subunits; GTP-binding protein gamma subunits; phosphatidylinositol 3-kinase; P-Rex1 protein; receptor protein-tyrosine kinases; receptors, G-protein-coupled

MeSH Terms

Cell Line, Tumor
*Cell Movement/drug effects
Enzyme Activation/drug effects
GTP-Binding Protein beta Subunits/*metabolism
GTP-Binding Protein gamma Subunits/*metabolism
Guanine Nucleotide Exchange Factors/metabolism
Humans
Lysophospholipids/pharmacology
Neoplasms/enzymology/*metabolism
Phosphatidylinositol 3-Kinases/*metabolism
Proto-Oncogene Proteins c-akt/metabolism
Receptors, G-Protein-Coupled/metabolism
Signal Transduction